TY - JOUR T1 - SPLUNC1 Degradation by the Cystic Fibrosis Mucosal Environment Drives Airway Surface Liquid Dehydration JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00668-2018 SP - 1800668 AU - Megan J. Webster AU - Boris Reidel AU - Chong D. Tan AU - Arunava Ghosh AU - Neil E. Alexis AU - Scott H. Donaldson AU - Mehmet Kesimer AU - Carla M.P. Ribeiro AU - Robert Tarran Y1 - 2018/01/01 UR - http://erj.ersjournals.com/content/early/2018/08/09/13993003.00668-2018.abstract N2 - Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which lead to diminished transepithelial anion transport, cause the multi-organ disease cystic fibrosis (CF). CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may up-regulate the epithelial Na+ channel (ENaC), further exacerbating dehydration. We previously demonstrated that the short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia. Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cultures (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment. We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Interestingly, normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-dervied peptide, SPX-101, resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum. Our data indicate CF mucosal secretions drive ASL hyperabsorption and protease-resistant peptides, like SPX-101, can reverse this effect to re-hydrate CF ASL.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Webster has nothing to disclose.Conflict of interest: Dr. Reidel has nothing to disclose.Conflict of interest: Dr. Tan has nothing to disclose.Conflict of interest: Dr. Ghosh has nothing to disclose.Conflict of interest: Dr. Alexis has nothing to disclose.Conflict of interest: Dr. Donaldson reports grants from Vertex Pharmaceuticals, grants from Parion Sciences, grants and personal fees from Nivalis Pharmaceuticals, personal fees from Pulmatrix, personal fees from Novartis Pharmaceuticals, personal fees from PTC Therapeutics, outside the submitted work; In addition, Dr. Donaldson has a patent Regulation of sodium channels by plunc proteins with royalties paid.Conflict of interest: Dr. Kesimer has nothing to disclose.Conflict of interest: Dr. Ribeiro has nothing to disclose.Conflict of interest: Dr. Tarran reports other from Spyryx Biosciences, outside the submitted work; In addition, Dr. Tarran has a patent Regulation of sodium channels by plunc proteins with royalties paid. ER -